We have found that estrogenic steroids and the adrenal steroid, dehydroepiandrosterone, protect cultured rodent cells against DMBA- and aflatoxin B1-induced cytotoxicity and malignant transformation, and also inhibit metabolism of (3H)DMBA to water-soluble products. Our observations are consistent with certain clinical findings in humans: 1. Burch et al. have reported a much reduced incidence of cancer in a group of 737 hysterectomized women on long-term estrogen replacement therapy. 2. Several investigators have obtained evidence that women with subnormal plasma levels of dehydroepiandrosterone may be predisposed to develop breast cancer. Others have shown that estradiol-17 beta is a competitive inhibitor of benzo(a)pyrene hydroxylase, and our hypothesis is that this steroid may protect in our system by competitively inhibiting carcinogen activation. Dehydroepiandrosterone has been shown to be a potent non-competitive inhibitor of glucose-6-phosphate dehydrogenase, the enzyme primarily responsible for generating extra-mitochondrial NADPH. We have also found that 7,8-benzoflavone, as well as several naturally occurring flavones (i.e., tangeretin, quercetin, etc.) protect cultured rat liver cells against DMBA and aflatoxin B1-induced cytotoxicity, possibly by competitively inhibiting carcinogen activation.